title: Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma.
abstract: Glaucoma is one of the most common neurodegenerative diseases. Despite this, the earliest stages of this complex disease are still unclear. This study was specifically designed to identify early stages of glaucoma in DBA/2J mice. To do this, we used genome-wide expression profiling of optic nerve head and retina and a series of computational methods. Eyes with no detectable glaucoma by conventional assays were grouped into molecularly defined stages of disease using unbiased hierarchical clustering. These stages represent a temporally ordered sequence of glaucoma states. We then determined networks and biological processes that were altered at these early stages. Early-stage expression changes included upregulation of both the complement cascade and the endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in complement component 1a (C1qa) were protected from glaucoma. Similarly, inhibition of the endothelin system with bosentan, an endothelin receptor antagonist, was strongly protective against glaucomatous damage. Since endothelin 2 is potently vasoconstrictive and was produced by microglia/macrophages, our data provide what we believe to be a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early molecular events, such as complement and endothelin induction, may provide effective new treatments for human glaucoma.
authors.affiliation: The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Howell
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Macalinao
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Sousa
authors.forename: Michael
authors.initials: M
authors.lastname: Walden
authors.forename: Ileana
authors.initials: I
authors.lastname: Soto
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kneeland
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Barbay
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: King
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Marchant
authors.forename: Matthew
authors.initials: M
authors.lastname: Hibbs
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
mesh_terms: D000818:Animals; D000077300:Bosentan; D016000:Cluster Analysis; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2 / Q000235:genetics* / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005901:Glaucoma / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009900:Optic Nerve / Q000503:physiopathology; D012160:Retina / Q000503:physiopathology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2; D013449:Sulfonamides; D015922:Complement C1q; D000077300:Bosentan